mangostin and Hemolysis

We recently reported the bioinspired synthesis of a highly potent nonpeptidic xanthone, 2c (AM-0016), with potent antibacterial activity against MRSA. Herein, we report a thorough structure-activity relationship (SAR) analysis of a series of nonpeptidic amphiphilic xanthone derivatives in an attempt to identify more potent compounds with lower hemolytic activity and greater membrane selectivity. Forty-six amphiphilic xanthone derivatives were analyzed in this study and structurally classified into four groups based on spacer length, cationic moieties, lipophilic chains, and triarm functionalization. We evaluated and explored the effects of the structures on their membrane-targeting properties. The SAR analysis successfully identified 3a with potent MICs (1.56-3.125 μ/mL) and lower hemolytic activity (80.2 μg/mL for 3a versus 19.7 μg/mL for 2c). Compound 3a displayed a membrane selectivity of 25.7-50.4. Thus, 3a with improved HC50 value and promising selectivity could be used as a lead compound for further structural optimization for the treatment of MRSA infection.

Topics: Adenosine Triphosphate; Anti-Bacterial Agents; Cell Survival; Cornea; Drug Design; Fibroblasts; Hemolysis; Humans; In Vitro Techniques; Membranes; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Structure-Activity Relationship; Xanthones

Based on the previously reported in vitro antiplasmodial activity of several xanthones from Garcinia mangostana, two xanthones, α-mangostin and a new compound, δ-mangostin, were isolated from mangosteen husk, and the in vitro antiplasmodial and cytotoxic effects were determined. α-Mangostin was more active against the resistant Plasmodium falciparum chloroquine-resistant (FCR3) strain (IC50  = 0.2 ± 0.01 μM) than δ-mangostin (IC50  = 121.2 ± 1.0 μM). Furthermore, the therapeutic response according to the administration route was evaluated in a Plasmodium berghei malarial murine model. The greatest therapeutic response was obtained with intraperitoneal administration; these xanthones reduced parasitemia by approximately 80% with a daily dose of 100 mg/kg administered twice a day for 7 days of treatment. Neither compound was effective by oral administration. Noticeable toxicological effects were not observed. In addition to the antimalarial effect of these xanthones isolated from G. mangostana husk, the availability of larger amounts of husk raw material to purify the bioactive xanthones is advantageous, permitting additional preclinical assays or chemical transformations to enhance the biological activity of these substances.

Topics: Animals; Antimalarials; Disease Models, Animal; Erythrocytes; Garcinia mangostana; Hemolysis; Humans; Injections, Intraperitoneal; Malaria; Mice; Mice, Inbred BALB C; Parasitemia; Plasmodium falciparum; U937 Cells; Xanthones

The emergence of methicillin-resistant Staphylococcus aureus (MRSA) has created the need for better therapeutic options. In this study, five natural xanthones were extracted and purified from the fruit hull of Garcinia mangostana and their antimicrobial properties were investigated. α-Mangostin was identified as the most potent among them against Gram-positive pathogens (MIC=0.78-1.56 μg/mL) which included two MRSA isolates. α-Mangostin also exhibited rapid in vitro bactericidal activity (3-log reduction within 5 min). In a multistep (20 passage) resistance selection study using a MRSA isolated from the eye, no resistance against α-mangostin in the strains tested was observed. Biophysical studies using fluorescence probes for membrane potential and permeability, calcein encapsulated large unilamellar vesicles and scanning electron microscopy showed that α-mangostin rapidly disrupted the integrity of the cytoplasmic membrane leading to loss of intracellular components in a concentration-dependent manner. Molecular dynamic simulations revealed that isoprenyl groups were important to reduce the free energy for the burial of the hydrophobic phenyl ring of α-mangostin into the lipid bilayer of the membrane resulting in membrane breakdown and increased permeability. Thus, we suggest that direct interactions of α-mangostin with the bacterial membrane are responsible for the rapid concentration-dependent membrane disruption and bactericidal action.

Topics: Animals; Anti-Bacterial Agents; Biophysics; Cell Membrane; Cytoplasm; Dose-Response Relationship, Drug; Ethidium; Fluoresceins; Fluorescent Dyes; Gram-Positive Bacteria; Hemolysis; Hydrophobic and Hydrophilic Interactions; Kinetics; Membrane Potentials; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Microscopy, Electron, Scanning; Models, Chemical; Organic Chemicals; Permeability; Rabbits; Time Factors; Xanthones